The application proposes to use data from an existing prospective, longitudinal clinical-neuropathological study, the Memory and Aging Project (MAP) to examine whether brain levels of mercury (Hg) and selenium (Se) are related to brain neuropathology (A, neurofibrillary tangles, cerebral infarcts, Lewy bodies), inflammation (microglia), and neural reserve (synaptic protein density), to clinical outcomes (cognitive function, motor function, mild cognitive impairment, Alzheimer disease), and to fish consumption measured in the years before death. Recent studies by this group and others suggest that consumption of fish and marine n-3 fatty acids may protect the brain against dementia and cognitive decline. Fish are also a source of the environmental toxin, methyl mercury (MeHg), and the oxidative neuroprotectant nutrient, Se. Studies of neurocognitive development have demonstrated that the beneficial effects of the n-3 fatty acid, DHA and Se consumed in fish are offset by high levels of MeHg. There is limited study on whether there are also deleterious effects on the aging human brain. This application requests funds to examine these relations further by analyzing Hg and Se in post-mortem brain tissue among 200 deceased MAP participants, all of whom have years of annually collected data on diet and clinical outcomes. The study will examine whether post-mortem brain levels of Hg and Se are associated with fish consumption in the years before death. The study will test the hypotheses: 1) that higher brain levels of Hg will be associated with greater neuropathology and inflammation, less neural reserve, and higher risk of MCI, AD, and cognitive and motor decline; 2) higher levels of Se will be associated with greater neural reserve, less neuropathology and inflammation, lower risk of MCI, AD, and cognitive and motor decline; 3) that Hg and Se have a synergistic effect on brain pathologies and clinical neurological outcomes, and 4) that fish consumption contributes to these associations. The population is encouraged to consume fish to protect against heart disease, stroke, and dementia. Results of this study will inform the public on whether Hg content of fish should be considered in these recommendations. PUBLIC HEALTH RELEVANCE: The growing older population is encouraged to consume fish to benefit health; however, the aging brain may be particularly vulnerable to the toxic effects of MeHg contained in fish. The current application will investigate the independent and co- dependent effects of brain levels of Se and Hg on brain health and neurological disease as well as to dietary consumption of fish. Whatever the study results, this will be important information to the public health.